The number of identified human degenerative diseases with involvement of mitochondrial malfunction is steadily increasing. Therefore, the need for a detailed understanding of the physiologic controls of mitochondrial function in the living cell has become urgent. The experiments and analyses proposed in this application aim to develop a quantitative and integrated understanding of mitochondrial performance in the living cell, with emphasis on the sensitivity to cytosolic (ADP), to metabolic state influenced by the type of substrate, and to altered cytosolic (Ca++). Non-invasive spectroscopic and oxygen polarographic measurements of mitochondrial function will be made in excised mouse EDL (fast-twitch) and SOL (slow-twitch) muscles at rest and during contractile activity. The mitochondrial (ADP) response functions will be determined under control and physiologically and pharmacologically altered conditions. Completion of the stated aims will establish a paradigm for approaching similar quantitative questions in other cells and tissues. Further, the energy balance algorithm developed will provide a general predictive and analytical tool in the study of cell energetics and the relation to normal cell function and disease.